The past decade has seen tremendous progress in the delivery of treatment of HIV-infected individuals worldwide. Better antiretroviral therapy (ART), improved laboratory monitoring, and evidence of ART as prevention have led to the possibility of beginning to reverse the AIDS pandemic. At the same time, limited resources worldwide have tempered the ability of the international community to optimally utilize these proven interventions. In 2004 and in 2008, NIAID awarded our research group funding to develop and expand the Cost-Effectiveness of Preventing AIDS Complications International (CEPAC-I) Model, a computer simulation of the natural history, clinical management, outcomes, and cost-effectiveness of HIV treatment in 3 resource- limited settings: South Africa, C?te d'lvoire, and India. In the last 5-year cycle of the project, this collaboration produced more than 105 original papers in peer-reviewed journals. In this continuation, we propose to further expand the CEPAC-I Model to reflect important developments in HIV/AIDS, and to address several of the most pressing questions in HIV care. We have three specific aims: Specific Aim 1: To examine the optimal packages of HIV care - ART initiation, monitoring strategies including use of point-of-care tests, and regimen sequencing - given varying resource constraints in South Africa, C?te d'Ivoire, India, and Brazil. We will create a new web-based 'metamodel' structure to allow clinical policy makers in other countries to access the capabilities of the CEPAC-I Model. Specific Aim 2: To define the benchmarks of clinical efficacy and cost by which new technologies - including long-acting ART and strategies for HIV eradication - may become viable and cost-effective options. We will perform analyses to establish performance requirements for new HIV treatments in resource-limited settings to be cost-effective. Novel modeling methods will incorporate patient heterogeneity as well as expanded probabilistic sensitivity analysis. Specific Aim 3: To project clinical outcomes, cost, and cost-effectiveness of detection and treatment for major co-morbidities in people with HIV, including hepatitis B and C viruses, TB, and hypertension. We will assess the cost-effectiveness of merging HIV care with screening and treatment for other common diseases in people with HIV. With new approaches to costing and budget impact analysis, we will assess the affordability of broadening HIV treatment programs. The assembled internationally-recognized, multidisciplinary research team has a lengthy record of disseminating findings to inform HIV care and guidelines, both in the US and internationally. To expand the project scope, we have added investigators from Brazil, the most HIV-affected country in Latin America. By leveraging the team's progress over the past 9 years and accomplishing the aims above, the proposed studies will answer many critical HIV clinical and policy questions facing the global HIV community.